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Would early treatment for everyone be better? Study poses the question

Gus Cairns

Published: 21 December 2011

A US study has found that patients infected with HIV in the
previous six months who were given 36 weeks (8.3 months) of antiretroviral
therapy (ART) were only a third as likely to need to go back on therapy over
the next two years than a comparator group of patients, who had not been given early therapy, were to need to
start it.

The study

The ACTG A5217 or Setpoint Study randomised 130
people who
had been infected with HIV more than one month but less than six months
before
diagnosis either to take 36 weeks of ART or
defer
treatment until treatment criteria were met. They excluded patients who already needed therapy due to low CD4 count,
high
viral load or AIDS-defining illness.

The initial aim of the study had been to see if a short period
of early
therapy produced a permanent reduction in the average viral load
patients have
off-treatment during chronic infection – their so-called viral ‘set
point’,
hence the name of the study.

This set point was due to be measured at week 72 of
the
study: that is, 72 weeks after diagnosis for both groups and 36 weeks
after
stopping therapy for those who took the short course.

Anticipating,
however,
that having had 36 weeks on therapy might produce better outcomes than
having
had none, a comparison was also due to be made between the viral load at
72
weeks in patients who had taken short-course therapy and at 36 weeks on
patients who had not taken it, in other words after 36 weeks of
uncontrolled
HIV viremia (detectable viral load in the blood) in both groups.

However the study was
stopped
early in August 2009 after 130 of a planned 150 subjects had been
recruited because twice as people than was anticipated, of those who had not had initial ART,
progressed to
the point when they needed to take it.

This
meant that the primary endpoint – viral load set point – could not be
determined as there were not enough patients left who had never taken
therapy
to provide a valid comparison.

Outcomes

There were however very significant differences
between
arms in terms of the proportion of patients who needed to start or re-start therapy. The criteria for starting or restarting ART were:

two consecutive CD4
counts below 350 cells/mm3 or one below 200 cells/mm3 or
with
a CD4 percentage below 14%;

a viral load over 700,000 more than a month
into the study or one over 200,000 more than three months into the
study;

Including all 130 participants, regardless of the
amount of
time they had been in the study, 36% (23 out of 64) of those who had not
taken
36 weeks of’ ART progressed to needing therapy versus 11% (seven out of 66)
of
those who had taken it.

The most common reason for initiating therapy was
low CD4
count (six on initial treatment and 13 on no initial treatment,
including one
with a CD4 count below 200 cells/mm3 and two with a CD4
percentage
below 14%).

The only other person who took initial ART who re-initiated
ART did
so because of chronic fatigue.

Of the other ten patients who did not
take
initial therapy and who had to start treatment, five did so because of a
high
viral load, one had both a high viral load and a low CD4 count, and four
had
HIV-related symptoms (two low platelets, one oral hairy leukoplakia and
one
persistent herpes symptoms). There were two deaths in the group not
given
initial therapy but neither appeared medically related to HIV (one was a
suicide).

However these 130 patients included some who had
only been in
the study for a short time. The primary analysis was therefore of 79
participants who had
been in
the study for more than 72 weeks when it
was stopped, half of whom had taken initial 36-week ART, .

Amongst this group only 10% of those given initial ART needed to re-start it, but 50% of those who had not
taken
initial ART needed to start it.

When patients who had not taken initial ART were
compared 36
weeks after study entry with patients who had taken initial ART 72 weeks after study entry (i.e. 36 weeks
after
stopping ART), 27.5% of those
not
given initial ART needed to start therapy versus 11% who had been
given
initial ART.

In other words, if patients took initial therapy
then
stopped it, they were only just over a third as likely to progress to
needing
ART in the next 36 weeks than patients who had never taken therapy were
in the
initial 36 weeks.

Discussion and
conclusions

Making a direct comparison in treatment outcomes
between the two arms of this study is difficult. On the one hand, comparing both groups at
week 72 of the study mainly proves that a short course of initial therapy puts off the time you need to start it – not a
surprising result. On the other hand, comparing the arms at week 36 off-therapy, while including all the patients who did not take initial ART, only includes those patients who did take ART who were in the study for at least 72
weeks before it was closed.

It also includes no comparator arm of patients who remained on ART, so no comparison can be
made between deferring lifetime treatment and initiating it.

The main surprise in the study was the speed at which people
off therapy progressed to needing it. One model based on the
CASCADE cohort (Lodi)
has predicted that 27% of patients will develop a CD4 count below 350 cells/mm3
within two years of seroconversion; in contrast, this study found that half of
patients not given initial therapy did.

The A5217 study may overestimate the speed
of progression because it mainly recruited patients who had seroconversion
symptoms; or the CASCADE study could underestimate progression because it
excluded people who had taken therapy in early infection and then stopped, thus
excluding the fastest progressors.

However, as the authors say, “If immediate therapy is not
begun, progression to meeting standard criteria for ART initiation may occur
more rapidly than expected...[this] contributes to the growing body of evidence
favouring earlier treatment.”

In an accompanying editorial, Tossonian and Conway point out
that the results of ACTG A5217 are compatible with the results from the SPARTAC
study (Fidler) which found that initial therapy also delayed subsequent therapy
but found that just under half of patients needed to start or restart therapy
within four years.

They comment that “it is not often possible or medically
indicated” for patients to start taking therapy at diagnosis, but that studies
like A5217 and SPARTAC show that the time to starting ART may be
considerably shorter, especially with changed CD4 criteria, than patients often
suppose; doctors now have the evidence to suggest they may have a year
to 18 months on average before they need to start ART, even if diagnosed early.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.